What is the role of DNA damage in healthy brain function and neurodegenerative disease? A new study delves into the relationship between double-strand DNA breaks and brain network activity. Learn more...

Progressive neuronal DNA damage in aging brains has been closely linked with
the onset of neurodegenerative disorders such as Alzheimer’s disease.
However, a new study suggests that one type of neuronal damage,
double-strand DNA breaks (DSBs), might also be a regular part of healthy
learning and memory functions.

“The most surprising to me is the ability of normal brain activity to increase
DNA breaks and the very rapid repair,” said Dr. Lennart Mucke, Director and
Senior Investigator at Gladstone Institutes, who led the study. “That
suggests this dynamic of breaking and repairing DNA is part and parcel of
normal brain activity, and we’re dying to find out what its meaning is.”

In a paper published in Nature Neuroscience, Mucke’s team also reported the
effects of two separate treatments for the accumulation of neuronal DSB
damage related to the brain’s overproduction of the amyloid-ß protein–a
protein thought to be a significant cause of Alzheimer’s.

“We demonstrated for the first time that blocking the abnormal brain network
activity that amyloid proteins cause can totally prevent the DNA breaks,”
said Mucke.

In the study, Mucke’s team observed two groups of mice–transgenic Alzheimer’s
model mice with increased levels of amyloid proteins and healthy controls.
The mice were introduced to new environments with different types of visual
stimulation for 2 hours and then placed back into their home cages to rest
for 24 hours.

Mucke and colleagues carefully analyzed nerve cells in different brain regions
that showed evidence for DSBs. By microscopy, the team was able to count the
number of neurons that had markers of DNA breaks. The results showed that
the mice’s activities led to an increase in DSBs, especially in the dentate
gyrus, a brain region that is involved in learning and memory. Within 24
hours, the breaks were found to be repaired in the healthy mice but not in
the mice with elevated levels of amyloid proteins.

“The amyloid proteins seemed to not only increase the number of breaks at
baseline by changing the activity pattern in the brain, but they also seem
to delay the repair when there had been an exploration-related increase in
the breakage,” said Mucke. “And over time that could of course lead to the
accumulation of DNA damage.”

During their investigation, the group also found that they could prevent
accumulation of the DNA damage caused by the amyloid proteins through two
different strategies. First, they were able to improve neuronal connectivity
in the Alzheimer’s-type mice using an FDA approved anti-epileptic drug
called Levetiracetam. Second, the team was able to regulate the tau protein,
which has been shown to cooperate with amyloid proteins in increasing DSB
levels.

According to Mucke, both methods may offer a solution to preventing the
increase in DNA breaks caused by the amyloid proteins. “[It’s] exciting
because it means that one can probably protect the DNA inside nerve cells
from at least some of the amyloid-related damage by changing the activity of
neuronal networks, which we achieved by these two different strategies,”
Mucke explained.

Mucke says that the findings could lead to future research into the role of
DSBs in neuroplasticity–the ability of the nervous system to adapt to
changes in the environment

But for now, Mucke and his lab are investigating whether these DSBs might
occur randomly in chromosomes or if they actually take place at very
specific sites involved in learning and memory.

“That’s a very interesting endeavor in an effort to better understand what
role [DSBs] might play,” said Mucke.